了解过敏原免疫疗法的机制

Amber Luong, MD, PhD
Associate Professor

Over 50 million of people suffer from allergies a year in the United States. Many control their symptoms with over-the-counter medications and avoidance measures. A subset of allergy sufferers, approximately 3 million, has found relief with allergen immunotherapy.

Similar to the concept of vaccinations, allergen immunotherapy causes changes in the immune response such that future encounters with the allergen incite mild to no allergy symptoms. The concept of treating hay fever allergies with injections of increasing amounts of ragweed allergen was first documented by Noon in 1911.¹该模型已成为现代皮下免疫疗法的基础。从那时起，已经学习了大量信息，包括对过敏原的免疫反应和免疫疗法的特定变化。

免疫系统的变化由于immunotherapy can be divided temporally into early, intermediate and late effects. Desensitization of mediator release from mast cells and basophils to allergen exposure is the first change noted with the initiation of allergen immunotherapy. The mechanism responsible for this desensitization has yet to be elucidated. As allergen dosing is increased in the course of immunotherapy, the next most notable response is a change in T cell subset distribution with the generation of allergen specific T regulatory (T reg) cells and a decrease in Th2 cells. Repeated allergen exposure stimulates IL-10 and TGF-β expression by allergen-specific, inducible, type 1, peripheral T regulatory (Tr1) cells, which act in an autocrine fashion to further activate these Tr1 cells and initiate peripheral tolerance. Finally, the late changes include decrease in IgE production by B cells and an increase in IgG4 and IgA serum levels. These changes are responsible for the clinical effect of ameliorating allergy symptoms.

过敏原免疫疗法引起的关键变化之一是产生T-REG细胞，导致周围耐受性。这种强调通过免疫疗法产生T-REG细胞的重要性代表了一种新的范式转移，因为曾经强调的是免疫疗法会导致TH1与Th2比率的变化。在那些非过敏个体中，健康的非过敏性与过敏个体的比较已经发现T REG细胞较高。³除了过敏个体中T型细胞的T reg次数失衡外，与健康对照相比，TH2 REG细胞的活性在抑制CD4+ T细胞方面的有效性较低。²The newly generated T reg cells from immunotherapy have several suppressive mechanisms including the expression of two cytokines, IL-10 and TGF-β.

逆转对过敏原的免疫和炎症反应涉及的关键细胞因子是IL-10。IL-10从诱导的T Reg细胞中分泌，显示了直接和间接抑制活性。首先，IL-10作用于B细胞，以诱导从IgE到IgA，IgG4和IgG1产生的免疫球蛋白同种型切换。另外，IL-10对肥大细胞和嗜碱性粒细胞具有抑制作用。最后，IL-10抑制了由肥大细胞，嗜碱性粒细胞和嗜酸性粒细胞释放的介质引起的炎症作用。IL-10的这些关键抑制作用不仅引起了该分子的新兴趣，不仅对过敏治疗，而且在其在癌症中的潜在作用。

我们自己的研究与IL-10在区分过敏反应与对过敏原挑战的健康反应中的关键作用是一致的。将过敏真菌鼻炎与健康对照个体与真菌抗原的外周血液单核细胞的反应相比，只有健康的非过敏个体对IL-10分泌的增加对真菌抗原挑战做出了反应。在AFRS患者中进行的其他研究将需要确定增加IL-10和T reg细胞是否代表任何将来治疗的目标效应。

Sublingual immunotherapy (SLIT) has gained some recent excitement as an alternative to subcutaneous immunotherapy (SCIT). Unlike subcutaneous immunotherapy that requires administration in a medical facility; sublingual immunotherapy has proven safe enough to be administered at home. Initial safety and efficacy studies have been performed in Europe. The immunologic mechanism of SLIT appears to be similar to SCIT, although the magnitude of the effects is significantly more modest.⁴在美国，SLIT未获得FDA批准。但是，美国许多研究正在进行中，如果在美国采用的话将导致过敏管理发生重大变化。这种变化很可能像在欧洲发生。我们将遵循这一发展。

References

1. Noon L. Prophylactic inoculation against hay fever.Int Arch Allergy Appl Immunol1953;4:285-8.
2. Akdis M，Verhagen J，Taylor A等。健康和过敏个体中的免疫反应的特征是过敏原特异性T调节1和T辅助2细胞之间的平衡。实验医学杂志2004; 199：1567。
3. Ling Em，Smith T，Nguyen XD等。CD4+ CD25+调节性T细胞抑制过敏原T细胞激活与过敏性疾病的特应状态和表达的关系。柳叶刀2004; 363：608-15。
4. 威尔逊D，利马M，达勒姆·S。过敏性鼻炎的舌下免疫疗法：系统评价和荟萃分析。过敏2005; 60：4-12。

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